The present invention relates to an improvement of a process for producing 2-(4-pyridyl)ethanethiol from 4-vinylpyridine and thiourea. 2-(4-Pyridyl)ethanethiol is a useful compound as an synthetic intermediate for medicaments and pesticides and also is a useful compound as a modifying agent for catalysts at the production of bisphenol A by condensing phenol and acetone.
Although a large number of reports have been hitherto published on the synthesis of pyridylalkylthiols, with regard to the synthesis of 2-(4-pyridyl)ethanethiol, a method of reacting 4-vinylpyridine with thiourea in the presence of p-toluenesulfonic acid in an ethanol solvent to form an isothiuronium salt and then converting it into 2-(4-pyridyl)ethanethiol in ammonia water is considered to be practical, which is described in Journal of Organic Chemistry (J. Org. Chem.), 26, 82 (1961), and an improvement of this method has been advanced (cf. Japanese Patent Laid-Open Nos. 228540/1999 and 255748/1999).
One problem in the process of reacting 4-vinylpyridine with thiourea in ethanol is the necessity of providing a reaction apparatus with a strong stirring means because the reaction solution becomes slurry owing to precipitation of the isothiuronium salt formed during the reaction. The other problem is that the isothiuronium salt should be recovered by solid-liquid separation from the reaction solution, washed, dried, and then converted into 2-(4-pyridyl)ethanethiol with ammonia water as the next step, and the operations are tedious and complex and take a long period of time. Furthermore, since an alcoholic organic solvent such as ethanol is used as a reaction solvent, a large quantity of organic waste is generated, which results in a large load on the environment.
Accordingly, it is an object of the invention to provide a process for producing 2-(4-pyridyl)ethanethiol which is free from such problems.
Paying attention to the fact that the isothiuronium salt as an intermediate of the reaction is water-soluble, the present inventors have found that 2-(4-pyridyl)ethanethiol can be produced by reacting 4-vinylpyridine with thiourea in an aqueous medium in a yield equal to that in the reaction in ethanol, without isolating or purifying the isothiuronium salt on the way.
Namely, according to the present invention, 2-(4-pyridyl)ethanethiol can be produced in simple operations and in good yields by reacting 4-vinylpyridine with thiourea in an aqueous medium containing an acid to form a solution containing an isothiuronium salt and then making the solution alkaline to convert the isothiuronium salt into 2-(4-pyridyl)ethanethiol. Moreover, since an aqueous medium is used as a reaction medium, organic waste can be reduced.
According to the present invention, 4-vinylpyridine is reacted with thiourea in an aqueous medium in the presence of an acid to form an isothiuronium salt. The reaction proceeds as follows. 
As the acid, use may be made of organic acids such as p-toluenesulfonic acid, benzenesulfonic acid, and trifluoromethanesulfonic acid and general inorganic acids such as sulfuric acid, hydrochloric acid, and nitric acid. Preferably, aromatic sulfonic acids such as p-toluenesulfonic acid and benzenesulfonic acid and sulfuric acid which are easy to handle are used. Of these, p-toluenesulfonic acid or sulfuric acid is preferably used.
The acid is used in such an amount that may be a stoichiometric amount shown in the above scheme or more based on 4-vinylpyridine, but since the use of an excess amount of the acid may induce a side reaction, the acid is preferably used in an amount of 4 equivalents or less, particularly 3 equivalents or less based on 4-vinylpyridine. In this connection, a higher concentration of the acid in the aqueous medium is preferable unless the easiness of the reaction operations is impaired, and in the case of p-toluenesulfonic acid, the concentration is preferably from about 5 to 50% by weight, particularly about 20 to 40% by weight.
Moreover, thiourea is used in a stoichiometric amount or an amount slightly more than the amount, and it is preferable to use it in an amount of 1.5 equivalents or less, particularly 1.3 equivalents or less.
The reaction may be effected by dissolving an acid and thiourea into an aqueous medium and then adding dropwise 4-vinylpyridine thereto under stirring. The reaction may be carried out preferably at an elevated temperature of 30 to 100xc2x0 C., particularly 50 to 100xc2x0 C. for 1 to 10 hours under an inert gas atmosphere such as nitrogen.
When the reaction of forming the isothiuronium salt is completed, the reaction solution is cooled to 50xc2x0 C. or lower and the solution is made alkaline by adding an alkali to convert the isothiuronium salt into 2-(4-pyridyl)ethanethiol. As the alkali, sodium hydroxide and the like may be used but ammonia is preferably used. When ammonia is used, the reaction proceeds as follows. 
Although a stoichiometric amount of required ammonia is two molar equivalents relative to the isothiuronium salt, but it is preferable to use an excess amount of ammonia, usually three molar equivalents or more relative to the isothiuronium salt for complete proceeding of the reaction. In this connection, since the acid used excessively in the previous step is also present in the isothiuronium salt solution, in addition to the amount required for neutralizing the acid, it is preferable to use ammonia in an amount of 3 to 15 molar equivalents, particularly 3 to 5 molar equivalents relative to 4-vinylpyridine used as a starting material. When the amount of ammonia is too large, the yield generally decreases. This is probably because 2-(4-pyridyl)ethanethiol formed causes a side reaction. Ammonia is usually used as ammonia water which is easy to handle, and the concentration may be determined in consideration of operability at following filtration and extraction steps.
The conversion of the isothiuronium salt into 2-(4-pyridyl)ethanethiol is completed under stirring at 30 to 70xc2x0 C. for about 0.5 to 10 hours. However, since the yield tends to decrease by the occurrence of a side reaction when a solution temperature is high at the addition of an alkali, it is preferable to maintain the solution at a temperature of 50xc2x0 C. or lower at the time when an alkali is added. However, when the solution temperature is low, the reaction rate of the conversion decreases. In order to avoid the decrease of the yield and accelerate the conversion, it is preferable that the solution is maintained at a temperature of less than 50xc2x0 C. at least until the solution reaches a neutral point and then warmed to a temperature of 50xc2x0 C. or higher.
After completion of the reaction, in the case that an aromatic sulfonic acid is used as the acid, the reaction product solution is cooled to about 10xc2x0 C. to precipitate a guanidinium salt formed as a by-product and an extraction solvent such as chloroform is further added thereto, followed by filtration to remove insoluble matter. The residue is further washed with the extraction solvent and the washing liquid is combined with the filtrate. Then, the filtrate is subjected to liquid separation and an extraction solvent phase is recovered. In the case that an inorganic acid such as sulfuric acid is used as the acid, no guanidinium salt precipitates by cooling and hence, in this case, a direct extraction operation with an organic solvent may be carried out without filtration.
In both cases, the aqueous phase is further extracted with an extraction solvent and the resulting extraction solvent phase is combined with the previously obtained extraction solvent phase. After removal of the extraction solvent therefrom, objective 2-(4-pyridyl)ethanethiol can be obtained by distilling the residual liquid under reduced pressure.